Of the purine and pyrimidine derivatives having an open oxygenated chain at the nitrogen atom, which can be considered nucleoside analogues with open sugar substituent, 9-(2-hydroxyethoxy methyl) guanine was found particularly effective in the treatment of diseases due to viral agents such as herpes simplex virus, herpes zoster virus and Epstein-Barr virus. More recently its usefulness was ascertained, in combination with other drugs, for the management of pathologies originated by retrovirus.
9-(2-hydroxyethoxy methyl) guanine was disclaimed by the British Patent no. 1523865 in 1974. Its preparation, described in Example no. 6 of the foregoing patent, is carried out by refluxing overnight guanine with a very large excess of hexamethyldisilazane (HMDS) (59 moles of HMDS per 1 mole of guanine), to obtain a 2,6,9-trimethylsilyl guanine derivative. The reaction is favoured by the presence of ammonium sulphate in a more than catalytic quantity (0.86 moles).
The HMDS excess is rendered indispensable by the nearly total guanine insolubility, only slowly and gradually dissolving as it reacts with HMDS. The excess of HMDS must then be eliminated by vacuum distillation, leading to extensive degradation, such as to hinder its recovery.
The raw silyl derivative is dissolved in benzene; elimination of ammonium sulphate is then carried out by filtration; triethylamine in benzene and 1 mole of 2-benzoyloxyethoxymethyl chloride are then added (II) EQU Cl--CH.sub.2 --O--CH.sub.2 CH.sub.2 --O--CO--O (II)
and the mixture is allowed to reflux overnight. Following evaporation of the solvent 2,6-bis (trimethylsilyl)-9-benzoyloxyethoxymethyl-guanine is obtained and the silylated protection groups are therefrom eliminated by brief reflux in ethanol. 9-benzoyloxyethoxymethyl guanine (III), obtained by evaporation of the ethanol, must be thoroughly washed with water, dried and twice crystallized, first from methanol and then from water. ##STR2##
The resulting derivative is finally treated in a pressure reactor with methanolic ammonia at 80.degree. C., so 9-(2-hydroxyethoxymethyl) guanine (I) is obtained, to be recrystallized from methanol.
All in all the process is very long and time consuming. Its complicated method entails the use of several reactors, even under pressure, and of various solvents, wasting of a costly reagent (HMDS), the necessity to crystallize the intermediate (III) twice, from methanol and from water, and the final product (V) from methanol, specially because of the formation of an isomer in which the oxygenated chain is bound to nitrogen in the position 7.
Moreover, the yields are definitely unsatisfactory: the yield of the intermediate (III) is 14% of the theoretical and the yield of the final product (I) is 75% with a total yield of 10.33% even though, according to a variance given in the same example no. 6, the use of an excess (1.6 moles) of the intermediate (II) increases the yield of (III) to 32% and the overall yield to 24.9%.
At any rate the yield remains absolutely insufficient and considered impossible to improve, so much so that the assignees of that patent attempted to realize an alternative syntheses. In fact, a later U.S. Pat. No. 4146715, discloses a new and more satisfactory process for the synthesis of 9-(2-hydroxyethoxy methyl) guanine (I) based on the treatment of N.sub.2, 9-diacylated guanine derivatives with reagents able to introduce the 2-acyloxyethoxymethyl chain in position 9. An additional process of hydrolysis leads to the final derivative (I), with industrially acceptable yields (56% and 75% respectively in the two specific preparation examples quoted), starting from the above mentioned N.sub.2, 9-diacylated guanine derivatives, which, at any rate, are to be laboriously prepared apart.
Spanish Patent no. 528049 reports more or less the same procedure of the previous British Patent no. 1523865 since, for instance, silylation of guanine is carried out with large quantities of pure HMDS, followed by alkylation under uncontrolled conditions, reflux in ethanol for deprotection from silyl radicals and final aminolysis in alcohol, all the procedure being reported with uncertain yields and no improvement over the prior art.